title: [Dimeric bisberzimidazoles: cytotoxicity and effects on DNA methylation in normal and cancer human cells].
abstract: Cancer cells are characterized by the hypermethylation of promoter regions of tumor suppressor genes. DNA methyltransferase inhibitors cause re-activation of these genes that allows considering DNA methyltransferases as targets for anticancer therapy. As it was previously shown by us, dimeric bisbenzimidazoles, DB(n), differing in length of the oligomethylene linker between the two bisbenzimidazole fragments (n--number of methylene groups in linker) effectively inhibit the methylation of DNA duplexes by murine methyltransferase Dnmt3a. Here, the cytotoxicity of some of these compounds, their penetration into cells and influence on the methylation of genomic DNA in fetal lung fibroblasts line F-977 and cervical cancer cells HeLa have been studied. In the 0-60 microM concentration range, only the DB(11) displayed a significant toxic effect on the normal cells, whereas the effect of DB(n) investigated on the cancer cells was not significant. Interestingly, the DB(1) and DB(3) to a small extent stimulate the proliferation of HeLa and F-977 cells, respectively. DB(1) and DB(3) display ability to penetrate into the nucleus of HeLa and F-977 cells and accumulate in various parts of the nuclei. DB(11) is not able to penetrate into the nuclei of these cells. The incubation of F-977 cells with 26 microM of DB(1) or DB(3) led to a decrease of the methylation of 18S rRNA gene, which is located in the region of DB(1) and DB(3) accumulation. A similar effect produces the same concentration of DB (3) in the F-977 cells. However, the overall level of genomic DNA methylation was not changed. These data suggest that DB(n) can be directed to act on specific genes demethylation and in the future may selectively inhibit the proliferation of cancer cells.
authors.forename: M V
authors.initials: MV
authors.lastname: Dariĭ
authors.forename: A R
authors.initials: AR
authors.lastname: Rakhimova
authors.forename: V N
authors.initials: VN
authors.lastname: Tashlitskiĭ
authors.forename: S V
authors.initials: SV
authors.lastname: Kostiuk
authors.forename: N N
authors.initials: NN
authors.lastname: Veĭko
authors.forename: A A
authors.initials: AA
authors.lastname: Ivanov
authors.forename: A L
authors.initials: AL
authors.lastname: Zhuze
authors.forename: E S
authors.initials: ES
authors.lastname: Gromova
mesh_terms: D000818:Animals; D006690:Bisbenzimidazole / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D012337:RNA, Ribosomal, 18S / Q000235:genetics
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D012337:RNA, Ribosomal, 18S; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006690:Bisbenzimidazole